1. Field of the Invention
This invention relates to a device and method for washing a plurality of wells in a multi-well container. This invention further relates to adapting such a washing device to automatic computer control. The present invention also relates to a method for purifying a plurality of chemical products simultaneously in a multi-well reactor plate.
2. Summary of the Related Art
With the increasing interest of biological and chemical libraries in recent years, multi-well containers have become a useful tool in research and clinical procedures for the screening and evaluation of multiple samples and for the synthesis of chemical compounds on a micro scale.
Multi-well plates typically have a plurality of plastic tubes arranged in rectangular planar arrays of 6xc3x978, 8xc3x9712, or 16xc3x9724. This allows the researcher or clinician to perform multiple experiments at the same time. The tubes of the multi-well container are usually compartmentalized or subdivided, each tube equally spaced from the next within the rectangular array. The tubes or wells are interconnected in some way via a base, which itself is made of some material impervious to water. For example, the wells can be molded directly into the base. Recently, an improved multi-well container has been designed wherein each tube or well has its own walls or septa, providing less of a chance of cross-contamination of wells (Robbins, U.S. Pat. No. 5,916,526).
Other multi-well plates may be positioned in circular arrays on turntables to allow for automation of chemical and biological experiments through the use of a probe affixed to a rotating arm (Bell et al., U.S. Pat. No. 5,814,377). While robotic systems have been developed for the addition(and withdrawal of chemical substances from individual tubes of a multi-well plate, the plate washing process is still performed manually or semi-annually on individual tubes. Such manual operation is very time consuming and subject to error, particularly with chemical assays. Specifically, unreacted starting materials must be washed from each cell to isolate the desired product so as to subject it to further chemical processes. The washing process usually involves rinsing each cell with a solvent and then removing the resulting unwanted solution. This step is repeated as often as necessary, usually employing a different solvent each time.
Many washing stations for various biological and chemical multi-assay devices have been developed. For example, U.S. Pat. No. 5,803,987 discloses a washing station for multiple dispensing and aspirating probes used in robotic systems involved in chemical synthesis. Other devices are used to wash blood cells by separating the unreacted reagents and cellular debris from the cells of interest (Chase et al., U.S. Pat. No. 5,840,253). Another device provides for a method for washing a U-shaped reaction tube by supplying and subsequently discharging a washing liquid twice, the second time at a slower rate than the first time to assure that none of the washing liquid remains on the inner wall of the tube (Sakagami et al., U.S. Pat. No. 4,444,598).
U.S. Pat. No. 4,931,400 discloses a device for pouring washing water onto a multi-well plate. The device consists of a tank with orifices to accommodate the wells of a plate. Water is forced into each of the wells from an inlet by a pushable surface portion made of elastic synthetic resin which, when force is applied downwardly, serves to eject the water simultaneously from the orifices into the respectively facing wells of the multi-well plate.
The drawback of the above-mentioned devices are that they do not provide for the application and removal of multiple washing solvents from multiple tubes in a multi-well plate in a simultaneous and efficient manner. This is particularly important with chemical reactor plates, where unreacted starting materials materials need to be removed from the desired product in the cells. An efficient and economic wash station that can chemically wash unreacted constituents out of each cell simultaneously, while leaving the desired product intact, is desired.
The present invention provides a washing station for a multi-well synthesis reactor plate. Specifically, it is an object of the invention to provide a manually operated wash station that can simultaneously apply a wash process to multiple cells of a multi-well synthesis reactor plate. It is another object of the invention to adapt a manually operated wash station to automatic computer control, thereby executing the wash process automatically after having been loaded and started manually. It is a further object of the invention to provide a method for simultaneously washing a plurality of wells in a multi-well container. It is yet another object of the invention to provide a method for purifying a plurality of chemical products simultaneously in a multi-well reactor plate.
The present invention provides a washing station for washing a plurality of cells in a multi-well container having one or more solvent control valves for controlling the flow of solvent into the wash station. The solvent control valves are in turn connected to a solvent manifold. The solvent manifold is also connected to an upper housing having at least one solvent distribution chamber in communication with the solvent manifold. A nozzle plate is positioned adjacent to the upper housing and against a respective solvent distribution chamber. A plurality of nozzles is connected to each nozzle plate. A receptacle having a solvent collection chamber capable of holding a reactor plate containing a plurality of reaction cells is provided for each solvent distribution chamber. The receptacle can be positioned with respect to the upper housing such that each reaction cell is aligned with one of the nozzles. A positive pressure control valve provides positive pressure to restrict flow of solvent out of the reaction cells and into the solvent collection chamber. Also, a negative pressure control valve provides a negative pressure to remove solvent from the reaction cells.
The present invention also provides a method for simultaneously washing a plurality of reaction cells in a multi-well reactor plate. At least one reactor plate with a plurality of reaction cells is placed into a solvent collection chamber of a receptacle. Then, the receptacle is moved into a position directly underneath an upper housing. The upper housing and receptacle are moved together such that they form a seal between the each reactor plate and the respective solvent collection chamber. At this point, each reaction cell of each reactor plate is aligned with a nozzle of a nozzle plate positioned between the upper housing and the receptacle. Positive pressure is then applied to each solvent collection chamber followed by the turning on of one or more solvent control valves until a desired amount of solvent or solvents is present in each reaction cell. The solvent is allowed to remain in the reaction cells for a period of time as is necessary to clean the cells. Negative pressure is then applied to each solvent collection chamber before the solvent is subsequently removed from the reaction cells.
The present invention also provides for a method for purifying a desired product in a multi-well reactor plate. Chemical compounds are formulated in a plurality of cells in a reactor plate to set up a plurality of chemical reactions. The chemical reactions are allowed to proceed to completion to afford a desired product, a resin support material to which the product is bound chemically, and unreacted constituents. The unreacted constituents are then removed by employing a wash station as mentioned above. Finally, the resin support material is cleaved from the desired product.
The invention will be better understood with the reference to the specification, accompanying drawings and specific examples.